Staying Ahead of the Game

Companies have put processes in place for complying with states’ drug pedigree requirements and are piloting the serialization of drug packaging, in an uncertain regulatory environment.

FDA’s pedigree mandate—set back by a court stay supporting secondary wholesalers opposed to exemptions given to primary wholesalers—has since been upheld in several court rulings. It remains to be seen whether the agency will now look to more vigorously enforce its pedigree regulation.

Since the 2007 enactment of the FDA Amendments Act (FDAAA), FDA has turned its attention to defining standards for a serialized standardized numerical identifier (SNI) and for supply-chain track and trace.

With California’s deadlines for an electronic pedigree system still years away, industry meanwhile is lobbying for federal legislation that would supersede states with a single pedigree requirement for paper-based or electronic transactions.

Though official guidance is still evolving, standards such as the drug pedigree messaging standard (DPMS) are being used for electronic pedigree transactions. Pilot testing of tagging solutions and systems for managing vast amounts of coded data are well under way at many manufacturers, wholesalers, contract packagers, and converters.

In Europe, requirements by EFPIA and from states within the EU are supporting the use of 2-D bar coding on unit-of-sale packaging. “EFPIA is driving the use of the 2-D bar code on secondary packaging of blisters, supplemented by tamper-evident seals on the cartons. The bar code is seen as an insufficient security solution by itself,” says Scott Denley, global product manager, Alcan Packaging-Kreuzlingen (Switzerland).

“We have customers in the UK equipping their lines with ink-jet printers to meet the CIP 13 directive from France,” he adds. The mandate requires 2-D codes bearing the product code, batch number, and expiry date on all pharmaceutical packages by 2011.

Larger drug firms are looking at in-line printing solutions, says Gregg Metcalf, industry market manager, strategic initiatives, Nosco Inc. (Gurnee, IL). “The larger players are looking to make the investment. Smaller firms and many mid-sized companies want to be supplied with preserialized product to limit capital spending. A recent pharmaceutical customer opted for this approach with us for 2-D coding of its unit-of-sale packaging. The capital expenditure for printer and verification systems isn’t nearly as great,” Metcalf says.

The DPMS standard developed by GS1 supports compliance with states’ chain of custody regulations. In this approach, electronic pedigree documents secured by digital signatures are passed with each transaction, providing at any point a document of previous owners tracing back to the manufacturer.

PEDIGREE ALTERNATIVES

For supporting the sharing of serialized data for tracking business events, GS1 is developing the EPCIS model. In this model, product pedigrees are captured on-demand when data are shared from EPCIS data repositories owned by those in the supply chain collecting data.

“DPMS was designed specifically to enable compliance with today’s U.S. pedigree laws by providing a secure way of tracing drugs through the supply chain,” says Dirk Rodgers, cochair of the GS1 EPC Global Drug Pedigree Messaging work group, and author of the RxTrace blog, www.rxtrace.com.

Rodgers says a key feature of a supply-chain tracking solution is the ability to verify each prior transaction back to the manufacturer and ensure all product history is available when it is received. “Using EPCIS the way it was intended will not allow a buyer of drugs to do this full verification of all previous transactions efficiently because the data needed are distributed across the supply chain,” Rodgers says.

“It is possible for every buyer to request all of that data and perform the necessary analysis, but that is less efficient than the DPMS approach where all the data are passed to the new buyer in a single pedigree message.”

GS1 is investigating an approach for meeting state pedigree requirements within an EPCIS network. Rodgers is co-author of a proposal for combining EPCIS and DPMS. The solution would satisfy regulatory requirements while providing the supply chain visibility of serialized transactions EPCIS is designed to support.

“[Such] a new track-and-trace approach based on EPCIS might not have some of the characteristics that the current laws require. You would have to get the states to accept it,” Rodgers says.

CEPHALON READIES RF USE

Cephalon is preparing to “go live” with RFID-tagged packaging early next year. The biopharma company is putting serialized RF tags on two Class II narcotic medicines, Fentora and Actiq, at the unit-of-sale level. Product is then tracked at the manufacturing plant and at Cephalon’s outsourced distribution facility, where coded packages are picked to shipping containers.

Cephalon moved to the carton-level coding following projects in which it tested out RF technology and warehouse-level tracking of cases and pallets. “We have viewed each stage of this process as a learning experience, and each stage has prepared us for the next round of pilot testing and implementation,” says Brian Brown, director, e-commerce logistics.

Fentora foil/foil blister packages are packed seven to a unit carton. Actiq lozenge sticks are packed in a three-count PVC/foil blister, with 30 Actiq lozenge sticks packed to a unit carton. Cephalon chose near-field UHF technology for the carton tagging and reading. “We have been in development of the carton-level tagging and data aggregation for two years, during which time huge strides have been made in the technology,” says Gerry Frank, senior director of packaging technology.

“Near-field UHF is widely used, and we found it to be very accurate. [Also] it provides us with a standard reader platform so we don’t have to use both HF and UHF readers throughout the plant,” Frank says.

Nosco supplies cartons with Gen 2 Raflatac satellite tags with Impinj Monza Speedway chips embedded into the cartons’ interior. “For the item-level folding carton, we are placing the tags in line into the interior of the carton, folding, gluing, and then verifying the manufacturer ID and that the tag is good. We try to do this as fast as humanly possible,” says Nosco’s Metcalf. Nosco supplies labels with Avery Dennison UHF Gen 2 tags for Cephalon’s case and pallet tagging.

Line data management is handled by the Systech Guardian and Advisor applications. “Systech was already on our lines with a camera verification system, so they were an existing supplier that the plant was comfortable with,” says Frank.

After cartoning, a Data Matrix code with a redundant EPC code is printed and verified, then the EPC number is coded to the RF tag and verified. The bar code, lot, and expiry information is ink-jet printed on the carton for one product. Nosco supplies a carton with a black box for laser ablating the tagging data on the second product.

The Systech system commissions the carton before proceeding to case packaging. After collating and loading to a case, each carton is read in the case, the case is RF-tagged with serial number and commissioned, and the carton numbers are aggregated to the case number. Palletized cases are read, and the pallet tag is encoded for case aggregation.

“We have to get a 100% read rate in order to commission the case. A key challenge was when to capture the cartons in the shipping case. We do that using an array of antennas along with certain safeguards to ensure that everything coming off the manufacturing line is read cleanly and associated with the case level. If all 24 cartons in the case do not report, the case is rejected,” Frank says.

Cephalon first implemented SAP in testing tagged cases and pallets at its Salt Lake City manufacturing plant. “In this pilot, we created the general infrastructure for the plant with the ability to communicate with the SAP AII infrastructure” says Frank.

PICKING TO SHIPPERS

Project partner ENC Inc. integrated the SAP AII with Systech’s line control system. The system of record for managing the serialized RF data and the aggregation of data on the packaging levels, AII provisions the EPC codes to Systech’s Guardian central line manager. Guardian in turn sends them to the Advisor stations managing the intelligent line devices.

ENC also helped implement a serialized shipping container solution at Cephalon’s 3PL that will be ready for the first quarter 2010 rollout, says Brown.

OAT Systems provides the technology for capturing the RF data on product being picked to the containers. ENC wrote the software for reaggregating product to a shipping container based on the order being delivered. The new aggregations are sent on to SAP AII.

“We take all of the observed tags and build a new tree structure for the order being shipped and marry that to the shipping container ID,” says Ismail Nalwala, CEO, ENC.

The system accounts for both serialized and nonserialized product. “When we start shipping out to wholesalers, if we don’t have serialized content, we can still support a nonserialized e-pedigree model,” says Brown.

Cephalon will use SupplyScape’s e-pedigree solution. “We need to identify our trading partners that wish to participate in the process of sharing serialized data throughout the supply chain. After doing so, we will work out the communication mechanisms required to provide the serialized information through the supply chain. At this point, we haven’t shipped anything RF-enabled to our customers. We will be reaching out to them in the immediate future,” Brown says.

“[Ultimately] for RFID to realize its full potential, we need the support of the whole supply chain,” he adds.

The ability to trace coded packages offers great promise, when supplemented with authentication solutions that add layers of security and enable investigators and consumers to immediately discover diverted or counterfeit product. Converters are offering an array of newer technologies, for the overt and covert discovery of product’s status.

Seen only with the aid of a microscope, Oliver-Tolas Micro Text is printed on films, foils, and medical-grade papers, appearing as a printed line to the naked eye.

“The customer liked the idea of a layered solution with both overt and covert features. It is placing orders in the first quarter of 2010 for authenticating and protecting a product worldwide. Through our partnership with Kodak, we are able to offer a very low-cost solution with minimal pass-through cost from the converter,” Chaplin says.

The system from Eastman Kodak and Merck KGaA features ultracovert Securalic security pigments from Merck placed in ink or varnish. Kodak handheld readers detect markers laid down in unique profiles in minute quantities. Joe Caruso, business development manager, brand security and marketing workflow solutions, Kodak (Stamford, CT), notes that the solution is “drop in,” requiring no ink formulation by the converter. “Brand owners like this, as there is no human interference,” he says.

Merck’s translucent pigments can be manipulated to expand color pallet options and support integration of the color shifting ink feature into a package’s design. “One of the reasons we have had a lot of success with this product is we offer a secure supply chain. We manage the marker platform and engineer and build the detection devices,” Caruso says.

“Many brands are not organized for counterfeit detection, enforcement, and supply chain security. The Solutions For Business Practice helps brands develop end-to-end security programs based on best practices,” Caruso says.

Catalent is offering the DigiTrack security and product tracking system from Complete Inspection Systems Inc. (CIS; Indiatlantic, FL). DigiTrack adds a unique covert watermark with encrypted code to existing packaging graphics. Consumers or investigators can then use standard mobile devices to confirm a package’s authenticity.

Based on Digimarc Corp.’s digital water marking technology, the system also features a marketing dimension, as consumers interactively engage with the brand owner. Once packages are confirmed as genuine, the user can be automatically referred to a Web site, for an example.

Catalent has printed samples of watermarked cartons, and its sales force is demonstrating the solution to pharma customers, says Eric Caro, manager, new product development, Catalent’s Printed Components business. “Consumers using this anticounterfeiting solution can take an active role in ensuring the products they are purchasing are authentic. Brand owners can track a product’s status to confirm the product is in the right location at the right time, Caro says.

“The beauty of this solution is the additional potential for marketing. The customer could send a consumer to a secure web site for a more interactive experience with the product. They might provide information on a drug’s counterindications or a diet or exercise program,” Caro adds.

Caro says that iPhones with 3.2 megapixel cameras are more than adequate for reading the digital watermarks. “We feel it is the right time for this technology. There are a tremendous amount of digital devices in use that can support the application,” he says.

For marking cartons or labels, the coded image is embedded into existing art work for adding to the printing plates. Woven into the art work using color or invisible inks, the watermarks are rendered invisible to the human eye.

Manufacturers will direct consumers, pharmacists, or other investigators to a Web site to download the software into the device. When the camera on the cellular phone is focused on the package, the device beeps when the watermark is recognized. Custom software from CIS is designed to users’ requirements such as requests for further overt or covert information or displaying a video presentation.

Brand owners can confirm a package’s validity for example by asking the consumer to provide the last four digits of the lot number, says Gary Parish, CIS’s president. “You can use multiple watermarks and require the user to know where the encrypted code is located, or we can come back and tell you where to find it. A second covert code can be placed for authentication only by the manufacturer,” Parish says.

When the user is being referred to a Web site for added information, “you can mark the cell phone with a code. When the user goes to the Web site, you are identifying the person allowed to look at the mark,” he adds.

Catalent is using CIS’s Auto Proof ID automated inspection and proof reading station for verifying all of the printed copy and the watermark coding. “Auto Proof ID provides added value because you are inspecting and confirming the presence of the security marking in one process,” Parish says.

Alcan Global Pharmaceutical Packaging and Rondo-Pak (Norristown, PA) have each begun offering the Cryptoglyph security solution from AlpVision SA (Vevey, Switzerland); (http://blog.pmpnews.com/?p=728). Standard electronic devices are used to read covert bit-mapped microdots printed across the package surface. Alcan has multiple customer projects in progress after having developed the ability to place the markings on flexible pharmaceutical blister packaging, says Denley.

In this system, microholes or microdots that are invisible to the naked eye are printed as part of the normal printing or varnish process on cartons, blister, and labels. The coding requires no modification to the original document or special inks or taggants.

In a typical application, printers will download a file with the Cryptoglyph from AlpVision’s Krypsos Web-based application hosted at the pharma customer’s premises, says Fred Jordan, CEO, AlpVision.

An investigator will scan the package using a flatbed document scanner and send the image to Krypsos via the Internet for instant authentication. “The analysis is automatic and does not require any action by the brand owner. The software directly takes control of the scanner, performs the scan, analyzes the image, and returns the authentication result,” Jordan says.

The solution supports 21 CFR Part 11 ERES enabling full traceability of the generated code to the supplier, the package coded, and when it was marked.

DOWN TO THE DOSE

With the infrastucture for tracking serialized product years away from completion, brand owners require solutions today. On-dose marking provides an added dimension of security to package overt and covert codes.

“The world is comfortable right now with package protection [which] does indeed remove a huge number of diverters and counterfeiters from the supply chain. But I think we are a decade away from a true e-pedigree system happening. And ultimately [such a] package-based system falls short of protecting the medication within,” says Dean Hart, executive vice president, NanoGuardian (Skokie, IL).

“People think, ‘if I protect the package, I protect the product.’ We know that’s not true. We have seen counterfeit medications in authentic packaging.”

On-dose marking addresses the loss of identifying information when product is repackaged, legitimately or otherwise. With its on-dose security solution, NanoGuardian provides tracking to the level of pharmacist dispensing, which isn’t called for in existing U.S. regulations.

“We are proactively auditing the supply chain with a solution that provides an early warning system for detecting diverted and counterfeit product. The NanoGuardian solution doesn’t require any participation from downstream partners,” says Hart. “You know immediately whether a pharmacy supplied diverted or counterfeit product. Then at the level of forensic marking, we can capture and report to the manufacturer encoded data such as product, manufacturing, and distribution information. This can be used for tracing the product’s source back through the supply chain.”

The solution combines NanoEncryption technology providing on-dose covert, overt, and nanoscale security features with a market monitoring program in partnership with market researcher SDI. Prescriptions obtained from a NanoGuardian Physician Panel are filled at randomly selected pharmacies and shipped to NanoGuardian’s authentication center for verification. “Most security experts agree that illegal diversion is the catalyst for counterfeiting. Diversion is the prerequisite for the greater crime of counterfeiting where patients’ health and safety is at risk. NanoGuardian addresses both diversion and counterfeiting with a single technology,” Hart says.

In a program of continuous sampling, a binomial distribution probability model is used. The level of random sampling is determined by two factors: an assumed intrusion rate, defined by NanoGuardian as the incidence of counterfeiting plus the incidence of diversion, and the level of confidence the manufacturer desires in detecting counterfeit or diverted doses.

“We have found that most manufacturers accept an intrusion rate of 1%, which is in line with WHO’s projection for counterfeiting in develeped countries. If the desired level of confidence for detecting that intrusion is 99.5 %, the model dictates that 527 samples must be taken the course of a year,” Hart says.

Hart says a U.S. pharma firm will adopt the NanoEncryption technology and tracking solution for a product launching next year into a segment that has been shown to have a high degree of counterfeiting.